ABSTRACT Our laboratory recently discovered that postnatal human epidermal keratinocytes (KC) could be reprogrammed into a neural crest (NC) fate without genetic introduction of transcription factors or reprogramming to the pluripotent state. The KC-derived NC (KC-NC) could be coaxed to differentiate into all functional NC derivatives including peripheral neurons, melanocytes, Schwann cells and mesenchymal stem cell derivatives (osteocytes, chondrocytes, adipocytes and smooth muscle cells). Upon transplantation into chicken embryos, KC-NC migrated along stereotypical pathways and gave rise to multiple NC derivatives. Here we propose to extend our findings to adult epidermal keratinocytes, provide mechanistic understanding of the NC reprograming process, and demonstrate the use of KC-NC derived Schwann cells for treatment of demyelinating disease. In aim 1, we will determine whether human adult epidermal keratinocytes can be reprogrammed into neural crest stem cells under defined conditions. Aim 2 will study the mechanism of KC reprogramming into NC fate. In aim 3, we will develop a highly efficient strategy to differentiate KC-NC into Schwann cells. The KC-NC Schwann cells will be employed for the treatment of demyelinating disease using a mouse model of congenital hypomyelinating disease that has become the gold standard for the assessment of myelinating cell preparations. This work represents a paradigm shift in stem cell biology as it demonstrates the plasticity of human epidermal cells to be reprogrammed into cells of common developmental origin ? both originate from the ectoderm - without genetic modification and under defined culture conditions. Finally, our work has the potential to provide a novel source of abundant, readily accessible, autologous stem cells for treatment of neurodegenerative diseases, for which cell sourcing remains a severe impediment hampering cell therapy approaches.